Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk

Elise P. Salerno, Davide Bedognetti, Ileana S. Mauldin, Donna H. Deacon, Sofia M. Shea, Joel Pinczewski, Joseph M. Obeid, George Coukos, Ena Wang, Thomas F. Gajewski, Francesco M. Marincola, Craig L. Slingluff

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.

Original languageEnglish
Article numbere1240857
JournalOncoImmunology
Volume5
Issue number12
DOIs
Publication statusPublished - 1 Dec 2016

Fingerprint

Ovarian Neoplasms
Melanoma
Mortality
Genes
Neoplasm Metastasis
Gene Expression
Neoplasms
Skin
Transducers
Databases
RNA
Calcium
Survival
filaggrin
Population
Proteins

Keywords

  • Adherens junction
  • cancer immunology
  • desmosome
  • filaggrin
  • immune privilege
  • immunosuppression
  • melanoma
  • ovarian cancer
  • TIL
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk. / Salerno, Elise P.; Bedognetti, Davide; Mauldin, Ileana S.; Deacon, Donna H.; Shea, Sofia M.; Pinczewski, Joel; Obeid, Joseph M.; Coukos, George; Wang, Ena; Gajewski, Thomas F.; Marincola, Francesco M.; Slingluff, Craig L.

In: OncoImmunology, Vol. 5, No. 12, e1240857, 01.12.2016.

Research output: Contribution to journalArticle

Salerno, EP, Bedognetti, D, Mauldin, IS, Deacon, DH, Shea, SM, Pinczewski, J, Obeid, JM, Coukos, G, Wang, E, Gajewski, TF, Marincola, FM & Slingluff, CL 2016, 'Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk', OncoImmunology, vol. 5, no. 12, e1240857. https://doi.org/10.1080/2162402X.2016.1240857
Salerno, Elise P. ; Bedognetti, Davide ; Mauldin, Ileana S. ; Deacon, Donna H. ; Shea, Sofia M. ; Pinczewski, Joel ; Obeid, Joseph M. ; Coukos, George ; Wang, Ena ; Gajewski, Thomas F. ; Marincola, Francesco M. ; Slingluff, Craig L. / Human melanomas and ovarian cancers overexpressing mechanical barrier molecule genes lack immune signatures and have increased patient mortality risk. In: OncoImmunology. 2016 ; Vol. 5, No. 12.
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abstract = "We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.",
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AU - Pinczewski, Joel

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AU - Coukos, George

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AU - Marincola, Francesco M.

AU - Slingluff, Craig L.

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AB - We have identified eight genes whose expression in human melanoma metastases and ovarian cancers is associated with a lack of Th1 immune signatures. They encode molecules with mechanical barrier function in the skin and other normal tissues and include filaggrin (FLG), tumor-associated calcium signal transducer 2 (TACSTD2), and six desmosomal proteins (DST, DSC3, DSP, PPL, PKP3, and JUP). This association has been validated in an independent series of 114 melanoma metastases. In these, DST expression alone is sufficient to identify melanomas without immune signatures, while FLG and the other six putative barrier molecules are overexpressed in a different subset of melanomas lacking immune signatures. Similar associations have been identified in a set of 186 ovarian cancers. RNA-seq data from 471 melanomas and 307 ovarian cancers in the TCGA database further support these findings and also reveal that overexpression of barrier molecules is strongly associated with early patient mortality for melanoma (p = 0.0002) and for ovarian cancer (p < 0.01). Interestingly, this association persists for FLG for melanoma (p = 0.012) and ovarian cancer (p = 0.006), whereas DST overexpression is negatively associated with CD8+ gene expression, but not with patient survival. Thus, overexpression of FLG or DST identifies two distinct patient populations with low immune cell infiltration in these cancers, but with different prognostic implications for each. These data raise the possibility that molecules with mechanical barrier function in skin and other tissues may be used by cancer cells to protect them from immune cell infiltration and immune-mediated destruction.

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